The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Mascarenhas, John; Verstovšek, Srđan

doi:10.1002/cncr.34222

Cited by 12 publications

(2 citation statements)

References 64 publications

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“…PI3Kδ is the most expressed PI3K isoform in MF CD34 + cells. Parsaclisib, a new generation PI3Kδinhibitor, is being tested in phase 3 clinical trials of MF in association with ruxolitinib 4 , 43 , 60 , 89 . However, the clinical trial has been recently discontinued due to a lack of efficiency on the reduction of spleen volume.…”

Section: Molecules In Clinical Developmentmentioning

confidence: 99%

Recent advances in therapies for primary myelofibrosis

Vainchenker,

Yahmi,

Havelange

et al. 2023

Fac Rev

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Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) form the classical BCR-ABL1 -negative myeloproliferative neoplasms (MPNs) that are driven by a constitutive activation of JAK2 signaling. PMF as well as secondary MF (post-ET and post-PV MF) are the most aggressive MPNs. Presently, there is no curative treatment, except allogenic hematopoietic stem cell transplantation. JAK inhibitors, essentially ruxolitinib, are the therapy of reference for intermediate and high-risk MF. However, presently the current JAK inhibitors behave mainly as anti-inflammatory drugs, improving general symptoms and spleen size without major impact on disease progression. A better understanding of the genetics of MF, the biology of its leukemic stem cells (LSCs), the mechanisms of fibrosis and of cytopenia and the role of inflammatory cytokines has led to new approaches with the development of numerous therapeutic agents that target epigenetic regulation, telomerase, apoptosis, cell cycle, cytokines and signaling. Furthermore, the use of a new less toxic form of interferon-α has been revived, as it is presently one of the only molecules that targets the mutated clone. These new approaches have different aims: (a) to provide alternative therapy to JAK inhibition; (b) to correct cytopenia; and (c) to inhibit fibrosis development. However, the main important goal is to find new disease modifier treatments, which will profoundly modify the progression of the disease without major toxicity. Presently the most promising approaches consist of the inhibition of telomerase and the combination of JAK2 inhibitors (ruxolitinib) with either a BCL2/BCL-xL or BET inhibitor. Yet, the most straightforward future approaches can be considered to be the development of and/or selective inhibition of JAK2V617F and the targeting MPL and calreticulin mutants by immunotherapy. It can be expected that the therapy of MF will be significantly improved in the coming years.

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Section: Molecules In Clinical Developmentmentioning

confidence: 99%

Recent advances in therapies for primary myelofibrosis

Vainchenker,

Yahmi,

Havelange

et al. 2023

Fac Rev

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“…Unfortunately, PMF remains an incurable disease with shortened-life expectation, except for eligible patients who undergo successful allogeneic stem cell transplantation [2]. While JAK inhibitors (JAKi), such as Ruxolitinib, have shown significant improvements, their efficacy is limited on reducing malignant clonal burden and MF progression [3]. Despite the homogenous mutational landscape of MPNs, the underlying pathobiological mechanisms of MF are not fully understood [4,5].…”

Section: Introductionmentioning

confidence: 99%

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

Calledda,

Malara,

Balduini

2023

Current Opinion in Hematology

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Purpose of review Myelofibrosis (MF) is primarily driven by constitutive activation of the Janus kinase/signal transducer of activators of transcription (JAK/STAT) pathway. While JAK inhibitors have shown to alleviate disease symptoms, their disease-modifying effects in MF are limited. The only curative treatment remains allogeneic stem cell transplantation, which can be applied to a minority of patients. As a result, there is a need to explore novel targets in MF to facilitate appropriate drug development and therapeutic pathways. Recent findings Recent research has focused on identifying novel signals that contribute to the abnormal cross-talk between hematopoietic and stromal cells, which promotes MF and disease progression. Inflammation and immune dysregulation have emerged as key drivers of both the initiation and progression of MF. A growing number of actionable targets has been identified, including cytokines, transcription factors, signalling networks and cell surface-associated molecules. These targets exhibit dysfunctions in malignant and nonmalignant hematopoietic cells, but also in nonhematopoietic cells of the bone marrow. The study of these inflammation-related molecules, in preclinical models and MF patient's samples, is providing novel therapeutic targets. Summary The identification of immunotherapeutic targets is expanding the therapeutic landscape of MF. This review provides a summary of the most recent advancements in the study of immunotherapeutic targets in MF.

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The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Mascarenhas

Verstovšek

2022

Cancer

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Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.

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The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Cited by 12 publications

References 64 publications

Recent advances in therapies for primary myelofibrosis

Recent advances in therapies for primary myelofibrosis

Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

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